CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages.
Bottom Line: Adoptive transfer of WT IMs increases the reduced number of lung metastasis foci in Ccl3 deficient mice.Mechanistically, Ccr1 deficiency prevents MAM retention in the lung by reducing MAM-cancer cell interactions.These data suggest that inhibition of CCR1, the distal part of this signaling relay, may have a therapeutic impact in metastatic disease with lower toxicity than blocking upstream targets.
Affiliation: MRC Centre for Reproductive Health, Queen's Medical Research Institute, the University of Edinburgh, Edinburgh EH16 4TJ, Scotland, UK.Show MeSH
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Mentions: To test our hypothesis that CCR2 acts as a signaling receptor in MAMs, we first identified potential downstream targets of CCR2 signaling in the MAMs. Previously, we reported that CD11b+ MAMs express a much higher level of CCR2 compared with CD11c+ pulmonary resident macrophages (Qian et al., 2009), suggesting that MAMs receive more CCR2 signal than resident macrophages. We therefore compared the gene expression profile of MAMs (F4/80+CD11b+) with those of resident macrophages in normal lung (Lng MΦ; F4/80+CD11c+) and similarly isolated splenic (Spl MΦ; F4/80+CD11b+) macrophages. Hierarchical clustering clearly separated MAMs from other resident macrophages, and identified 37 genes whose expression was significantly higher in MAMs (Fig. 1, A and B). To narrow down the candidates, we compared mRNA levels of these genes between WT and Ccr2-deficient macrophages and found eight genes whose expression was significantly reduced in Ccr2-deficient macrophages (Fig. 1 C). Notably, one of these genes encodes the CC-chemokine ligand 3 (CCL3), a high-affinity ligand for CCR1 (Neote et al., 1993) whose expression in myeloid cells is associated with metastasis of colon cancer and lymphoma cells (Kitamura et al., 2010; Rodero et al., 2013). It is also reported that CCL3 enhances intracellular calcium flux in human macrophages but not monocytes (Kaufmann et al., 2001), suggesting that CCL3 might possess specific roles in macrophage functions. We thus hypothesized that activation of CCL2–CCR2 signaling prompts macrophages to secrete CCL3, which regulates prometastatic functions of MAMs.
Affiliation: MRC Centre for Reproductive Health, Queen's Medical Research Institute, the University of Edinburgh, Edinburgh EH16 4TJ, Scotland, UK.